title: Intrathecal injection of adenosine 2A receptor agonists reversed neuropathic allodynia through protein kinase (PK)A/PKC signaling.
abstract: A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in a chronic constriction injury (CCI) model of neuropathic pain. We aimed to determine if this long-term reversal was induced by A2AR agonism versus more generalized across adenosine receptor subtypes, and begin to explore the intracellular signaling cascades involved. In addition, we sought to identify whether the enduring effect could be extended to other models of neuropathic pain. We tested an A1R and A2BR agonist in CCI and found the same long duration effect with A2BR but not A1R agonism. An A2AR agonist (ATL313) produced a significant long-duration reversal of mechanical allodynia induced by long established CCI (administered 6 weeks after surgery), spinal nerve ligation and sciatic inflammatory neuropathy. To determine if ATL313 had a direct effect on glia, ATL313 was coadministered with lipopolysaccharide to neonatal microglia and astrocytes in vitro. ATL313 significantly attenuated TNFα production in both microglia and astrocytes but had no effect on LPS induced IL-10. Protein kinase C significantly reversed the ATL313 effects on TNFα in vitro in microglia and astrocytes, while a protein kinase A inhibitor only effected microglia. Both intrathecal PKA and PKC inhibitors significantly reversed the effect of the A2AR agonist on neuropathic allodynia. Therefore, A2AR agonists administered IT remain an exciting novel target for the treatment of neuropathic pain.
authors.affiliation: Department of Psychology and Neuroscience, Center for Neuroscience, University of Colorado-Boulder, Boulder, CO, USA. Electronic address: lisa.loram@me.com.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Loram
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Taylor
authors.forename: Keith A
authors.initials: KA
authors.lastname: Strand
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Harrison
authors.forename: Rachael
authors.initials: R
authors.lastname: Rzasalynn
authors.forename: Paige
authors.initials: P
authors.lastname: Sholar
authors.forename: Jayson
authors.initials: J
authors.lastname: Rieger
authors.forename: Steven F
authors.initials: SF
authors.lastname: Maier
authors.forename: Linda R
authors.initials: LR
authors.lastname: Watkins
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006930:Hyperalgesia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D007278:Injections, Spinal; D008026:Ligation; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000627:therapeutic use; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020426:Sciatic Neuropathy / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: C510376:ATL 313; D058908:Adenosine A2 Receptor Agonists; D010880:Piperidines; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C
keywords: ATL313; Astrocytes; Interleukin-10; Intrathecal; Mechanical allodynia; Microglia; Protein kinase; Rats